Kinesin is a motor protein which slides over microtubules using adenosine triphosphate and transports, for example, organelles and vesicles, playing an important role in a diverse variety of cell biological processes such as cell division and intracellular substance transportation (e.g., nerve axonal transportation).
At present, about 100 kinds of kinesin-like proteins have been identified. These proteins are presumed to play a very important role during mitosis of the cell cycle by directly interacting with microtubules or chromosomes of the mitotic spindle.
Cell division is a phenomenon that is indispensable for organisms to live and maintain homeostasis of internal environment. Meanwhile, it is also important that apoptosis occurs in organisms to maintain homeostasis. That is, cell division (proliferation) and apoptosis occurring in a balanced manner maintain homeostasis of internal environment of organisms.
However, when such a balance between cell division and apoptosis is lost to enhance cell division, cell proliferative diseases such as cancer develop.
In view of this, attempts have been made to inhibit the kinesin as a treating method for cell proliferative diseases such as cancer. Chemotherapeutic agents routinely used for treating cancer are, for example, taxanes and vinca alkaloids. Taxanes and vinca alkaloids act on microtubules existing in various kinds of cell structures. Presumably, these drugs break the mitotic spindle to inhibit division of cancer cells and induce death of the cancer cells.
Microtubules, however, have an important role not only in cancer cells but also normal cells such as nerve cells. Therefore, these routinely-used chemotherapeutic agents do not specifically target the mitotic spindle, causing problematic side effects of nerve disorders such as numbness in limbs.
A kinesin spindle protein (also called KSP, Eg5, KNSL1, TRIP5 or KIF11, for example), which is one of the identified kinesin-like proteins, is known to localize at the mitotic spindle and be responsible for formation and functions of the bipolar mitotic spindle (see Anne Blangy et al., “Phosphorylation by p34cdc2 regulates spindle association of human Eg5, a kinesin-related motor essential for bipolar spindle formation in vivo” Cell, Vol. 83, pp. 1159-1169, 1995).
Eg5 is known to involve the development of neurons of mice but disappears from neurons immediately after birth, suggesting that the inhibition of Eg5 does not cause peripheral nerve disorders accompanied by routinely-used chemotherapeutic agents (see Lotfi Ferhat et al., “Expression of the mitotic motor protein Eg5 in postmitotic neurons: implications for neuronal development” Journal of Neuroscience 18(19), pp. 7822-7835, 1998).
Therefore, at present, demand has arisen for the provision of a low-molecular-weight new compound capable of inhibiting a kinesin spindle protein with high efficiency; a kinesin spindle protein inhibitor containing the low-molecular-weight compound; and a pharmaceutical composition containing the kinesin spindle protein inhibitor, capable of preventing or treating disorders mediated at least partially by a kinesin spindle protein, free of adverse side effects, and having high safety.